Very little is known about how the immune system is altered by inherited genetic immunodeficiencies. However, congenital immunodeficient patients as well as patients made immunodeficient by cancer chemotherapy and/or other disease states are very susceptible to opportunistic microbial agents. The xid immunodeficiency in CBA/N mice when combined with studies on the immune regulation of anti-phosphocholine (PC) antibodies represents an ideal model system in which to: 1) study how an immune deficiency alters a highly restricted well defined antibody response; and 2) learn the ways one can manipulate both the ontogeny and the response potential of the immune system to overcome this immune deficient state. Antibodies to PC have been shown to protect mice against lethal infections by Streptococcus pneumonia (9-11), and mice which carry the xid immune deficiency are highly susceptible to S. pneumonia because they fail to produce anti-PC antibodies. In this research proposal, a series of studies have been proposed: 1) to elucidate the cellular defects responsible for loss of the protective anti-PC immune response in xid mice; and 2) to manipulate the ontogeny and development of PC-specific B cell precursor in xid mice so that this anergic state can be overcome. The information obtained from these studies could be directly applicable to patients who are immunologically compromised and therefore highly susceptible to life threatening microbial infection. We will attempt to overcome the immune deficient state to PC in xid mice by: 1) altering the in vivo and in vitro ontogeny of Lyb 5- - T15+ B cells; 2) polyclonally activating the PC-specific B cell precursors prior to antigenic stimulation, and 3) by focusing anti-T15-idiotypic antibodies and T cell help onto T15+ B cells. The anti-PC antibodies produced by xid mice will also be analyzed to determine their amino acid sequence and fine specificity of binding for PC-analogues.